Murine Leukemias with Retroviral Insertions at Lmo2 Are Predictive of the Leukemias Induced in SCID-X1 Patients Following Retroviral Gene Therapy

Utpal P Davé,Rati Tripathi,Susan M Cleveland,Marshall S Horwitz,Neal G Copeland,Mary A Thompson,James R Downing,Ming Yi,Nancy A Jenkins,Keiko Akagi,Robert Stephens

doi:10.1371/journal.pgen.1000491

Abstract

Five X-linked severe combined immunodeficiency patients (SCID-X1) successfully treated with autologous bone marrow stem cells infected ex vivo with an IL2RG-containing retrovirus subsequently developed T-cell leukemia and four contained insertional mutations at LMO2. Genetic evidence also suggests a role for IL2RG in tumor formation, although this remains controversial. Here, we show that the genes and signaling pathways deregulated in murine leukemias with retroviral insertions at Lmo2 are similar to those deregulated in human leukemias with high LMO2 expression and are highly predictive of the leukemias induced in SCID-X1 patients. We also provide additional evidence supporting the notion that IL2RG and LMO2 cooperate in leukemia induction but are not sufficient and require additional cooperating mutations. The highly concordant nature of the genetic events giving rise to mouse and human leukemias with mutations at Lmo2 are an encouraging sign to those wanting to use mice to model human cancer and may help in designing safer methods for retroviral gene therapy.

Highlights

SCID-X1 patients are deficient in the common c chain of the interleukin-2 receptor (IL2RG) [1]
We have found two leukemias that have retroviral insertions near Lmo2 and Il2rg in the same cell
Our data show that Lmo2 and Il2rg cooperate but may not be sufficient for leukemia development and additional mutations contribute to leukemia development

Summary

Introduction

SCID-X1 patients are deficient in the common c chain of the interleukin-2 receptor (IL2RG) [1]. In three SCID-X1 trials, CD34+ hematopoietic stem cells were cultured ex vivo and transduced with a defective Moloney murine leukemia virus (MuLV) expressing IL2RG and transplanted back to the patients. LMO2 is a T-cell oncogene [6], suggesting that these leukemias resulted from insertional mutagenesis. SCID-X1 is caused, in part, by a failure of T-cell production, and the infusion of immature gene-corrected CD34+ cells into SCID-X1 patients favors the engraftment of the T-cell lineage over other lineages. This could explain why T-cell leukemias predominate in these patients. A murine T-cell leukemia with insertional mutations at Lmo and Il2rg has been reported [9]. While IL2RG is not overexpressed in SCID-X1 leukemias [3] or in the mouse leukemia with an Il2rg insertion, subtle effects on its expression, such as an inability to downregulate its expression during T cell development, could be oncogenic [10]

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